title: CD8(+) T Cells Are Required For Glatiramer Acetate Therapy in Autoimmune Demyelinating Disease.
abstract: The exact mechanism of glatiramer acetate (GA, Copaxone®), an FDA-approved immunomodulatory therapy for multiple sclerosis (MS), remains unclear after decades of research. Previously, we have shown that GA therapy of MS induces CD8(+) T cell responses that can potentially suppress pathogenic CD4(+) T cell responses. Using a murine model of MS, experimental autoimmune encephalomyelitis (EAE), we now demonstrate that CD8(+) T cells are necessary in mediating the therapeutic effects of GA. Further, adoptive transfer of GA-induced CD8(+) T cells resulted in amelioration of EAE, establishing a role as a viable immunotherapy in demyelinating disease. Generation of these cells required indoleamine-2,3-dioxygenase (IDO), while suppressive function depended on non-classical MHC class I, IFN-γ, and perforin expression. GA-induced regulatory myeloid cells, previously shown to activate CD4(+) regulatory T cells in an antigen-independent manner, required CD8(+) T cells for disease suppression in vivo. These studies demonstrate an essential role for CD8(+) T cells in GA therapy and identify their potential as an adoptive immunotherapeutic agent.
authors.affiliation: Department of Pathology, University of Texas Southwestern Medical Center, Dallas, Texas, United States of America.
authors.forename: Andrew F
authors.initials: AF
authors.lastname: Tyler
authors.forename: Jason P
authors.initials: JP
authors.lastname: Mendoza
authors.forename: Mihail
authors.initials: M
authors.lastname: Firan
authors.forename: Nitin J
authors.initials: NJ
authors.lastname: Karandikar
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects* / Q000276:immunology / Q000378:metabolism; D003602:Cytotoxicity, Immunologic / Q000187:drug effects; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000209:etiology / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D005260:Female; D051858:Forkhead Transcription Factors / Q000378:metabolism; D000068717:Glatiramer Acetate / Q000494:pharmacology*; D015395:Histocompatibility Antigens Class I / Q000378:metabolism; D007167:Immunotherapy; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D007371:Interferon-gamma / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D063308:Myelin-Oligodendrocyte Glycoprotein / Q000633:toxicity; D010446:Peptide Fragments / Q000633:toxicity; D050378:T-Lymphocytes, Regulatory / Q000166:cytology / Q000378:metabolism
chemical_list: D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; D015395:Histocompatibility Antigens Class I; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D063308:Myelin-Oligodendrocyte Glycoprotein; D010446:Peptide Fragments; D000068717:Glatiramer Acetate; D007371:Interferon-gamma